Field of the Invention
The present invention relates to gas-generating nanoparticles containing fine-grained calcium carbonate (FCC) crystals and a biocompatible polymer.
Background of Technique
Many contrast agents have been widely developed and used for clinical practice such as X-ray, Ultrasound, MR, CT, and PET [Journal of Clinical Oncology 2008; 26(24):4012-4021, European Journal of Nuclear Medicine 2000; 27(6):619-627, Expert Opinion on Drug Metabolism & Toxicology 2009; 5(4):403-416]. Toxicity of the agents including renal-toxicities, nausea, hair loss, renal disorder, nephropathy, and nephrogenic systemic fibrosis, has limited their use in clinical cases [Clinical Journal of the American Society of Nephrology 2007; 2(2):264-267, Investigative Radiology 2008; 43(2):141-144]. Although various contrast agents can be improved by polymeric coating and target-ligand conjugation, the potential toxicity still remains and must be resolved.
Recently, non-toxic carbon dioxide gas have attracted considerable attention as a contrast agent [European Journal of Radiology 2006; 60(3):324-330, Pharmaceutical Research 2010; 27(1):1-16, Artificial Cells, Blood Substitutes and Biotechnology 1988; 16(1-3):411-420].
Ultrasound imaging is obtained by acoustic signal based on backscattering or reflection of sound above 20 KHz, and utilized for estimation of organs anatomically and functionally in the body [Heart 1997; 77(5):397-403, European Radiology 2001; 11(8):1316-1328, Ultrasonic Imaging 1979; 1(3):265-279]. The imaging technique has attractive properties such as no insertion or surgery, simplicity, real-time imaging, and low cost as diagnosis tools [Current Opinion in Pulmonary Medicine 2003; 9(4):282-290]. Microbubbles have been applied to ultrasound imaging as contrast agents, however it is inherently unstable and have large sizes during blood circulation [Journal of Biomaterials Science, Polymer Edition 2011; 22(4-6):417-428]. In addition, microbubbles are difficult to functionalize with bioactive molecules.
In the case of classic anti-cancer drugs such as chemical agents and genes, they have confronted with severe side effects due to drug effects on normal tissues [New England Journal of Medicine 2003; 348(6):538-549]. Cancer cells also tend to show drug resistance, leading to vicious cycle of repetitive treatments with high dosage because of reduced effect of subsequent therapy [Annual Review of Medicine 2002; 53(1):615-627]. It is well-known that the cell live and death are controlled by apoptotic and/or necrotic cell death pathways [Cell death and differentiation 1995; 2(2):87-96, Current Opinion in Cell Biology 2004; 16(6):663-669, Oncogene 2004; 23(16):2757-2765]. Meanwhile, cancer therapy focused on the drugs were concerned with not necrotic-cell death pathways but apoptotic the pathways. Necrosis has been considered as accidental and unregulated cell death signaling, but it could be induced by ischemia condition, microbial infection, neuronal excitotoxins, or reactive oxygen species were reported [The Journal of Experimental Medicine 1998; 188(5):919-930, Cell Death and Differentiation 2003; 10(1):45-65].
Despite the various anticancer drugs associated with the cancer cell apoptosis pathway have been consistently developed, they have a technical limitation from complexity of their apoptotic process or acquisition of drug resistance by changing their micro environment. Furthermore, a anticancer drug treatments are considered a secondary treatment because nonspecific anticancer drugs may be accumulated on normal cells and adversely affect the cells.